Integrins are transmembrane .alpha..beta. heterodimer receptors that are expressed on a wide variety of cells. They mediate adhesion of cells to extracellular matrix ("ECM"). There are eight known .beta. subunits and fourteen known a subunits, which associate in various combinations to form at least twenty receptors with different ligand specificities. The ligands for several of the integrins are adhesive extracellular matrix (ECM) proteins such as fibronectin, vitronectin, collagens and laminin.
It is becoming increasingly clear that the ECM influences gene expression and that changes in the expression of genes encoding matrix proteins alter the composition of the ECM. Integrins appear to mediate messages from the exterior of a cell to its interior, thereby inducing changes in gene expression. In this capacity, the integrins control many medically important biological phenomena, including cell migration during development, tissue repair, cancer cell differentiation, metastasis of tumor cells, platelet aggregation, homing of immune system cells and the extension of neuronal processes to target sites.
Many integrins, including .alpha..sub.5 .beta..sub.1, .alpha..sub.v .beta..sub.5, .alpha..sub.IIb .beta..sub.3 and .alpha..sub.v .beta..sub.3 recognize the amino acid sequence RGD (arginine-glycine-aspartic acid), which is present in fibronectin and other adhesive proteins.
Fibronectin is the only known ECM ligand for the .alpha..sub.5 .beta..sub.1 integrin and the binding of fibronectin to this integrin is mediated by an RGD sequence. In contrast, the integrins .alpha..sub.v .beta..sub.3 and .alpha..sub.IIb .beta..sub.3, which also recognize the RGD sequence, can bind many different adhesive proteins.
The .alpha..sub.5 .beta..sub.1 integrin is important in promoting the assembly of fibronectin matrix and initiating cell attachment to fibronectin. Similarly, .alpha..sub.v .beta..sub.3, .alpha..sub.v .beta..sub.5, and .alpha..sub.IIb .beta..sub.3 integrins are important in promoting cell attachment to vitronectin, fibrinogen, fibronectin, osteopontin and some other RGD-containing proteins. Peptides and protein fragments containing the RGD sequence can be used to modulate the activity of the RGD-recognizing integrins. The use of RGD peptides permits targeted modulation and manipulation of cell adhesion and other integrin-mediated cellular events in various medical situations, including platelet aggregation, thrombosis, wound healing, osteoporosis, tissue repair and tumor invasion. Ruoslahti, J. Clin. Invest., 87:1-5 (1991).
While RGD peptides that bind to more than one of the RGD-directed integrins have been used in some of these applications, the most developed application, anti-thrombotic use, depends on peptides that are more selective for the targeted integrin. The anti-thrombotic peptides target the platelet integrin .alpha..sub.IIb .beta..sub.3 (e.g. Collen et al., Thromb. Haemos., 71:95-102 (1994)).
Thus, a need exists for ligands that bind integrins selectively. The present invention satisfies this need and provides related advantages as well.